This revised R01 A1 proposal (AA022493), Consequences of Adolescent Alcohol Use on Brain Development, responds to the need to understand the impact of initiating alcohol consumption on adolescent brain maturation. We have teamed with the Center for Adolescent Substance Abuse Research (CeASAR) and Boston Children's Hospital to implement an innovative strategy that combines multiple neuroimaging and neuropsychological approaches to identify neurodevelopmental vulnerabilities associated with early and escalating alcohol use during adolescence. Adolescents will be recruited from general pediatrician offices and adolescent medicine clinics comprising the New England Partnership for Substance Abuse Research (NEPSAR), a practice-based research network of primary care offices. Adolescents will be enrolled into the study prior to the initiation of alcoho use or other drug use, and examined longitudinally, at baseline (13-14 yrs old) and again at two annual follow-up visits. To provide a comprehensive longitudinal profile of brain function, structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and task and resting state blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) will be paired with magnetic resonance spectroscopy (MRS) to measure GABA and glutamate levels in the anterior cingulate cortex (ACC) and medial temporal lobe (MTL, containing hippocampus). In addition, arterial spin labeling (ASL) will be used to measure quantitative perfusion, which will be used to calibrate the magnitude of BOLD fMRI signal changes during response inhibition and spatial memory fMRI tasks. Magnetic resonance measures will be integrated with measures from clinical assessments and an extensive neuropsychological battery, designed to detect and further characterize developmental changes and the influence of adolescent alcohol use. The incorporation of complementary multi-modal measures of brain function and neuroplasticity could offer valuable insight into the dynamic processes of brain maturation and help identify neural signatures associated with the onset and escalation of alcohol use, which will provide a foundation for informing prevention and intervention efforts aimed at reducing adolescent alcohol consumption.